Targeting c-MYC with Stapled Peptide IDP-121: A Promising Therapeutic Approach for Myeloma

Multiple myeloma (MM), a malignancy originating from B cells, has seen improved survival rates with autologous stem cell transplants and new therapies, yet remains incurable with a tendency to relapse. The c-Myc protein, often overactivated in cancers including MM due to various genetic alterations, has been challenging to target clinically due to its nuclear location and disordered structure.

The study introduces IDP-121, a stapled peptide designed to target the c-MYC protein. It has been shown to reduce the viability of numerous MM cell lines primarily through apoptosis, with rapid cellular uptake allowing a short contact time to be effective. This effect was mirrored in primary cells from MM patients, while normal lymphocytes were largely spared, indicating a potential therapeutic window.

IDP-121 rapidly disrupts the c-MYC/MAX complex as confirmed by immune-precipitation and FRET experiments, leading to a decrease in c-MYC protein levels without affecting gene expression, suggesting a direct impact on the protein. This results in the nuclear depletion of c-MYC and reduced DNA binding by the transcription factor complex.

In vivo studies demonstrate significant tumor growth reduction in MM models, with HPLC-MS and IHC analyses confirming effective distribution and target engagement in tumor tissue, marked by decreased c-MYC protein and cell proliferation. Importantly, IDP-121 was found to enhance the effects of standard MM treatments like bortezomib and dexamethasone.

The research suggests that IDP-121 could represent a first-in-class c-MYC inhibitor for MM, with potential applications in solid tumors as well. Having shown drug-like properties and passed GLP toxicology studies with no major systemic toxicity, IDP-121 is poised to enter Phase 1 clinical trials, offering a new therapeutic strategy for Myc-targeted cancer treatment.